Case Reports

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 60-year-old Cambodian woman presented with recurrent fever (temperature, up to 38.8°C) 7 months after receiving a kidney transplant secondary to polycystic kidney disease. Fever was attributed to recurrent pyelonephritis of the native kidneys while on mycophenolate mofetil, tacrolimus, and prednisone. As a result, she underwent a bilateral native nephrectomy and was found to have peritoneal nodules. Pathology of both native kidneys and peritoneal tissue revealed caseating granulomas and acid-fast bacilli (AFB) diagnostic for kidney and peritoneal tuberculosis (TB). She had no history of TB, and a TB skin test (purified protein derivative [PPD]) upon entering the United States from Cambodia a decade earlier was negative. Additionally, her pretransplantation PPD was negative.

Treatment with isoniazid, ethambutol, pyrazinamide, and levofloxacin was initiated immediately upon diagnosis, and all of her immunosuppressive medications—mycophenolate mofetil, tacrolimus, and prednisone—were discontinued. Her symptoms subsided within 1 week, and she was discharged from the hospital. Over the next 2 months, her immunosuppressive medications were restarted, and her TB medications were periodically discontinued by the Tuberculosis Control Program at the Department of Health (Philadelphia, Pennsylvania) due to severe thrombocytopenia. During this time, she was closely monitored twice weekly in the clinic with blood draws performed weekly.

Approximately 10 weeks after initiation of treatment, she noted recurrent subjective fever (temperature, up to 38.8°C) and painful lesions on the right side of the flank, left breast, and left arm of 3 days’ duration. Physical examination revealed a warm, dull red, tender nodule on the right side of the flank (Figure 1) and subcutaneous nodules with no overlying skin changes on the left breast and left arm. A biopsy of the lesion on the right side of the flank was performed, which resulted in substantial purulent drainage. Histologic analysis showed an inflammatory infiltrate within the deep dermis composed of neutrophils, macrophages, and giant cells, indicative of suppurative granulomatous dermatitis (Figure 2). Ziehl-Neelsen stain demonstrated rare AFB within the cytoplasm of macrophages, suggestive of Mycobacterium tuberculosis infection (Figure 3). A repeat chest radiograph was normal.

Comment

Clinical Presentation
Cutaneous TB is an uncommon manifestation of TB that can occur either exogenously or endogenously.¹ It tends to occur primarily in previously infected TB patients through hematogenous, lymphatic, or contiguous spread.² Due to their immunocompromised state, solid organ transplant recipients have an increased incidence of primary and reactivated latent TB reported to be 20 to 74 times greater than the general population.^3,4 One report stated the total incidence of posttransplant TB as 0.48% in the West and 11.8% in endemic regions such as India.⁵ The occurrence of cutaneous TB is rare among solid organ transplant recipients.¹ On average, a diagnosis of latent TB is made 9 months after transplantation because of the opportunistic nature of M tuberculosis in an immunosuppressed environment.⁶

TB Subtypes
Cutaneous TB can be in the form of localized disease (eg, primary tuberculous chancre, TB verrucosa cutis, lupus vulgaris, smear-negative scrofuloderma), disseminated disease (eg, disseminated TB, TB gumma, orificial TB, miliary cutaneous TB), or tuberculids (eg, papulonecrotic tuberculid, lichen scrofulosorum, erythema induratum).⁷ Due to the pustular epithelioid cell granulomas and AFB positivity of the involved cutaneous lesions, our patient’s TB can be classified as a metastatic TB abscess or gummatous TB.⁷

Metastatic TB abscess, an uncommon subtype of cutaneous TB, generally is only seen in malnourished children and notably immunocompromised individuals.^2,8,9 In these individuals, systemic failure of cell-mediated immunity enables M tuberculosis to hematogenously infect various organs of the body, resulting in alternative forms of TB, such as gummatous-type TB.¹⁰ One study reported that of the 0.1% of dermatology patients presenting with cutaneous TB, only 5.4% of these individuals had the rarer gummatous form.⁷ These metastatic TB abscesses begin as a single or multiple nontender subcutaneous nodule(s), which breaks down and softens to form a draining sinus abscess.^2,8,9 Abscesses are most commonly seen on the trunk and extremities; however, they can be found nearly anywhere on the body.⁸ The pathology of cutaneous TB lesions demonstrates caseating necrosis with epithelioid and giant cells forming a surrounding rim.⁹

Diagnosis
Diagnosis may be difficult because of the vast number of dermatologic conditions that resemble cutaneous TB, including mycoses, sarcoidosis, leishmaniasis, leprosy, syphilis, other non-TB mycobacteria, and Wegener granulomatosis.⁹ Thus, confirmatory diagnosis is made via clinical presentation, detailed history and physical examination, and laboratory tests.¹¹ These tests include the Mantoux tuberculin skin test (PPD or TST) or IFN-γ release assays (QuantiFERON-TB Gold test), identification of AFB on skin biopsy, and isolation of M tuberculosis from tissue culture or polymerase chain reaction.¹¹Given our patient’s history, clinical presentation, and the identification of mycobacteria with AFB stain, the diagnosis of cutaneous gummatous TB was confirmed.

At-Risk Populations
The recommendation for the identification of at-risk populations for latent TB testing and treatment have been clearly defined by the World Health Organization (Table).¹² Our patient met 2 of these criteria: she had been preparing for organ transplantation and was from a country with high TB burden. Such at-risk patients should be tested for a latent TB infection with either IFN-γ release assays or PPD.¹²These recommendations are supported by the American Thoracic Society, which specifies that a positive PPD test in a solid organ transplant recipient is defined as having induration greater than 5 mm.¹³ However, even with a high index of suspicion, it has been reported that as many as 75% to 80% of organ recipients who developed TB had a false-negative pretransplantation PPD due to anergy from immunosuppression.¹⁴ Given the notable risk for TB in organ transplant recipients on immunosuppressive medications, these patients should receive screening tests with high sensitivity and specificity, while controlling for possible anergy. Unfortunately, the role of anergy testing in the diagnosis of latent TB is not well defined, and thus not recommended at this time.^13,15 It is recommended to repeat PPD testing 7 to 10 days after the first test as a booster effect to rule out false-negative results.¹⁵

Finally, thrombocytopenia is an infrequent, life-threatening complication that can be acquired by immunocompromised patients on anti-TB therapy.¹⁷ Drug-induced thrombocytopenia can be caused by a variety of medications, including rifampicin, isoniazid, ethambutol, and pyrazinamide. Diagnosis of drug-induced thrombocytopenia can be confirmed only after discontinuation of the suspected drug and subsequent resolution of the thrombocytopenia.¹⁷ Our patient initially became thrombocytopenic while taking isoniazid, ethambutol, pyrazinamide, and levofloxacin. However, her platelet levels improved once the pyrazinamide was discontinued, thereby suggesting pyrazinamide-induced thrombocytopenia.

Conclusion

The risk for infectious disease reactivation in an immunocompromised patient undergoing transplant surgery is notable. Our findings emphasize the value of a comprehensive pretransplant evaluation, vigilance even when test results appear negative, and treatment of latent TB within this population.^16,18,19 Furthermore, this case illustrates a noteworthy example of a rare form of cutaneous TB, which should be considered and included in the differential for cutaneous lesions in an immunosuppressed patient.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Case Report

A 31-year-old black woman presented with a slow-spreading pruritic rash on the right thigh of 1 year’s duration. She had previously seen a dermatologist and was prescribed triamcinolone acetonide cream 0.1% and mupirocin ointment 2% but declined a biopsy. Review of symptoms was negative for any constitutional symptoms. Family history included hypertension and eczema with a personal history of anxiety. Clinical examination revealed grouped flesh-colored to light pink papules and plaques within a hyperpigmented patch on the right medial thigh (Figure 1).

Histopathology
A punch biopsy was negative for fungal, bacterial, or acid-fast bacilli culture. Histopathologic evaluation demonstrated a dense dermal infiltrate of large histiocytes admixed with inflammatory cells composed predominantly of lymphocytes and plasma cells. The histiocytes within the inflammatory infiltrate had vesicular nuclei and abundant eosinophilic cytoplasm (Figure 2A). Areas of emperipolesis were noted (Figure 2B). The large histiocytes stained positive for S-100 protein (Figure 2C) and negative for CD1a.

Comment

Rosai-Dorfman disease (also known as sinus histiocytosis with massive lymphadenopathy) is a non–Langerhans cell histiocytosis.¹ There are 2 main forms of RDD: one form that affects the lymph nodes and in certain cases the extranodal organs, and the other is purely CRDD. Cutaneous RDD is extremely rare and the etiology is unknown, though a number of viral and immune causes have been postulated. Cutaneous RDD presents as solitary or numerous papules, nodules, and/or plaques. Treatment options include steroids, methotrexate, dapsone, thalidomide, and isotretinoin, with varying efficacy reported.¹

Extranodal forms occur in 43% of RDD cases, with the skin being the most common site.¹ Other extranodal sites include the soft tissue, upper and lower respiratory tract, bones, genitourinary tract, oral cavity, gastrointestinal tract, orbits, testes, and rarely central nervous system involvement.²

Cutaneous RDD and RDD may be distinct clinical entities. Cutaneous RDD has a later age of onset than RDD (median age, 43.5 years vs 20.6 years) and a female predominance (2:1 vs 1.4:1). It most commonly affects Asian and white individuals while the majority of patients with RDD are of African descent with rare reports in Asians.¹

The etiology of CRDD remains unknown with hypotheses of viral and immune causes such as human herpesvirus 6, Epstein-Barr virus, and parvovirus B19. The polyclonal nature of the cell infiltrate and the clinical progression of RDD suggest a reactive process rather than a neoplastic disorder.¹ Rosai-Dorfman disease has been hypothesized to be closely related to autoimmune lymphoproliferative syndrome, an inherited disorder associated with defects in Fas-mediated apoptosis.⁵

Histologic findings in CRDD are similar to those in RDD, with a superficial and deep perivascular infiltrate of lymphocytes and plasma cells. A diffuse and nodular dermal infiltrate of foamy histiocytes exists in a background infiltrate of lymphocytes and plasma cells. Foamy histiocytes may be seen in dermal lymphatics, and lymphoid follicles with reactive germinal centers also may be present. Emperipolesis, the presence of intact inflammatory cells within histiocytes, is common in CRDD. Less often, histiocytes may contain plasma cells, neutrophils, and red blood cells. Mitoses and nuclear atypia are rare. Cutaneous RDD histiocytes stain positive for S-100 protein, CD4, factor XIIIa, and CD68, and negative for CD1a. Birbeck granules are absent on electronic microscopy of CRDD tissue, eliminating Langerhans cell histiocytosis.^1,3,5

The clinical diagnosis of CRDD is hard to confirm in the absence of lymphadenopathy. The lesions in CRDD may be solitary or numerous, usually presenting as papules, nodules, and/or plaques. More rarely, the lesions may present as pustules, acneform lesions, mimickers of vasculitis and panniculitis, macular erythema, large annular lesions resembling granuloma annulare, or even a breast mass.^1,3 One case report with involvement of deep subcutaneous fat presented with flank swelling beneath papules and nodules.⁶

The most common site of lesions in CRDD is the face, with the eyelids and malar regions frequently involved, followed by the back, chest, thighs, flanks, and shoulders.^1,5 Rarely, CRDD may be associated with other disorders, including bilateral uveitis, antinuclear antibody–positive lupus erythematosus, rheumatoid arthritis, hypothyroidism, lymphoma, and human immunodeficiency virus.¹

Numerous treatments have been attempted, yet the response often is poor. Because RDD is a benign and self-limiting disease, less aggressive therapeutic approaches should be used, if possible. Surgical excision of the lesions has been helpful in certain cases.⁶ Cryotherapy and local radiation, topical steroids, or laser treatment also have been found to improve the condition.^1,7 For refractory cases, dapsone and thalidomide have been effective. Mixed results have been observed with isotretinoin and imatinib; some patients improved whereas others did not. Utikal et al⁸ described a patient with complete remission of CRDD after receiving imatinib therapy; however, a different study reported a patient with CRDD who was completely resistant to this treatment.⁹ One case presenting on the breast did not respond to topical steroids, acitretin, and thalidomide but later responded to methotrexate.¹⁰

Conclusion

Cutaneous RDD is an unusual clinical entity with varied lesions. Generally, CRDD follows a benign clinical course, with a possibility of spontaneous remission. Further studies are required to confidently classify the etiology and variance between both RDD and CRDD.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Eccrine porocarcinoma (EPC), originally described by Pinkus and Mehregan¹ in 1963, is an exceedingly rare sweat gland tumor most commonly seen in older patients. Fewer than 300 cases have been reported in the literature, and it is believed to represent only 0.005% to 0.01% of cutaneous malignancies.² In the absence of established guidelines, wide local excision (WLE) has traditionally been considered the standard of treatment; however, local recurrence and nodal metastasis rates associated with WLE have been reported as high as 20%.³ More recently, a number of case reports and small case series have demonstrated higher cure rates with Mohs micrographic surgery (MMS), though follow-up is limited.^3-5 We describe a case of EPC presenting as a recurrent wart in a 36-year-old man that was successfully treated with MMS.

Case Report

A 36-year-old man with no notable medical history presented with a 0.5×0.5-cm, asymptomatic, flesh-colored, hyperkeratotic, polypoid papule on the right medial thigh (Figure 1). The lesion was diagnosed as a wart and treated with cryotherapy by another dermatologist several years prior to presentation. Dermatoscopic examination at the current presentation showed a homogenous yellow center with a few peripheral vessels and a faint pink-tan halo (Figure 2). Our differential diagnosis included a recurrent wart, fibrosed pyogenic granuloma, irritated intradermal nevus, skin tag, and adnexal neoplasm. A shave biopsy was performed. Histopathologic analysis revealed multiple aggregations of mildly pleomorphic epithelial cells emanating from the epidermis, with many aggregations containing ductal structures (Figure 3). Rare necrotic and pyknotic cells were present, but no mitotic figures or lymphovascular invasion were identified. Immunohistochemical staining was positive for carcinoembryonic antigen and epithelial membrane antigen but negative for Ber-EP4. These findings were consistent with a well-differentiated EPC.

The patient was offered MMS or WLE, with or without sentinel lymph node biopsy (SLNB). He opted for MMS. The initial 1-cm margin taken during MMS was sufficient to achieve complete tumor extirpation, and the final 3.7×2.5-cm defect was closed primarily. The MMS debulking specimen was sent for permanent sectioning and showed a small focus of residual tumor cells, but no mitoses or lymphovascular invasion were seen. The patient was referred to surgical oncology to discuss the option of SLNB, which he ultimately declined. He also was offered regional or whole-body positron emission tomography–computed tomography (PET-CT) to rule out metastatic disease, which he also declined. There was no evidence of recurrence or lymphadenopathy 19 months postoperatively.

Comment

Eccrine porocarcinoma is an exceptionally rare adnexal neoplasm that most commonly affects older adults. The average age at diagnosis is 71 years in men and 75 years in women.² Our case is rare because of the patient’s age. Benign eccrine poromas occur most frequently on the palms, soles, axillae, and forehead where eccrine density is highest; EPC occurs most frequently on the lower extremities.⁶ It may arise de novo or from malignant transformation of a preexisting benign poroma. Clinically, EPC may present as an asymptomatic pink-brown papule, plaque, or nodule and may have a polypoid or verrucous appearance, as in our patient. Ulceration is common.⁷ The differential diagnosis often includes nodular basal cell carcinoma, squamous cell carcinoma, pyogenic granuloma, and seborrheic keratosis.

Histologically, EPCs are characterized by aggregations of cohesive basaloid epithelial cells forming eccrine ductal structures.² Cellular atypia may be extremely subtle but, if present, can be helpful in differentiating malignant from benign lesions. Features of basal and squamous cell carcinoma also may be present. Definitive diagnosis is frequently based on the overall invasive architectural pattern.⁵ Robson et al² examined 69 cases of EPC for high-risk histologic features and concluded that tumor depth greater than 7 mm, mitoses greater than 14 per high-power field, and the presence of lymphovascular invasion were independently predictive of mortality. Moreover, after adjusting for mitosis and depth, an infiltrative border vs a pushing border was strongly predictive of local recurrence.² Immunohistochemical stains, although not necessary for diagnosis, may have utility as adjunctive tools. Cells lining the ducts within EPCs commonly stain positive for carcinoembryonic antigen, though glandular myoepithelial cells stain positive for S-100. Negative Ber-EP4 staining helps to differentiate EPC from basal cell carcinoma. Abnormal expression of p53 and overexpression of p16 also has been described.⁴

The rarity of EPC has precluded the development of any evidence-based management guidelines. Historically, the standard of care has been WLE with 2- to 3-cm margins. A review of 105 cases of EPC treated with WLE showed 20% local recurrence, 20% regional metastases, and 12% distant metastasis rates.⁸ Mohs micrographic surgery, which allows examination of 100% of the surgical margin vs less than 1% for WLE with the standard bread-loafing technique, might be expected to achieve higher cure rates. A review of 29 cases treated with MMS monotherapy demonstrated no local recurrences, distant metastasis, or disease-specific deaths with follow-up ranging from 19 months to 6 years.⁵ One case was associated with regional lymph node metastases that were treated with completion lymphadenectomy and adjuvant radiation therapy.⁷ The high mortality rate of patients with nodal disease has led some to recommend PET-CT and SLNB for patients with EPC. However, the prognostic value of such procedures has not been clearly defined and there is no demonstrated survival benefit for treatment of widespread disease. Our patient declined both SLNB and PET-CT, and our plan was to follow him clinically with symptom-directed imaging only.

Conclusion

Patients with EPC generally have a favorable prognosis with prompt diagnosis and complete surgical excision. Although most commonly seen in elderly patients, EPC may present in younger patients and may be clinically and histologically nondescript with little cytologic atypia. Based on a small but growing body of literature, MMS appears to be at least as effective as WLE as a primary treatment modality for EPC, while offering the advantage of tissue sparing in cosmetically or functionally important areas.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Hailey-Hailey disease (HHD), also known as benign familial chronic pemphigus, is an autosomal-dominant genodermatosis caused by mutations of the ATPase secretory pathway Ca²⁺ transporting 1 gene, ATP2C1.¹ It is characterized by crusted macerated erosions and velvety, fissured, hypertrophic plaques classically involving the intertriginous areas. The diagnosis is suggested by characteristic clinical morphology, involvement of the intertriginous areas, and a positive family history. Histology often confirms the diagnosis and demonstrates a characteristic dilapidated brick wall appearance. If there is a need to distinguish HHD from pemphigus, direct immunofluorescence studies also should be performed, which would be negative.^2,3 However, HHD often is misdiagnosed due to lack of knowledge of this uncommon disorder and its resemblance to other dermatoses of the intertriginous areas.⁴ We present an unusual presentation of HHD with late onset and involvement of the skin of the abdomen and foot.

Case Report

A 61-year-old woman presented with a 3×4-cm fissured plaque with erosions and a peripheral yellow crust on the left side of the anterior abdomen (Figure 1A). There was another fissured plaque with surrounding erythema and scaling on the fifth digit of the right foot (Figure 1B). For the last 11 years, she periodically experienced erosive and scabbing skin plaques under the breasts and on the axillae and groin. Her mother and maternal grandfather had a history of similar skin lesions. Due to a suspicion of HHD, a skin biopsy specimen of the abdominal plaque was performed, which demonstrated epidermal acanthosis and suprabasal acantholysis with lacunae formation (Figure 2). There was uneven thickening of the epidermal keratin layer with parakeratotic nests. The upper layer of the dermis demonstrated edema and focal fibrosis, enlarged capillaries, and pericapillary lymphohistiocytic infiltration with eosinophils and neutrophils. Accordingly, a diagnosis of HHD was established.

Comment

Hailey-Hailey disease occurs in 1 to 4 per 100,000 individuals without predilection for sex or ethnic group.^5-9 Onset usually occurs after puberty, most commonly in the third decade of life.^8,10-12 Mutations of the ATP2C1 gene on band 3q22.1 cause haploinsufficiency of Ca²⁺/Mn²⁺−ATPase protein 1 (hSPCA1) that alters the intracellular calcium gradient, leading to disruptions in assembly and trafficking of desmosomal proteins to the cell membrane. Consequently, altered intercellular connections and acantholysis of the epidermis occur.^1,13-16

Hailey-Hailey disease initially manifests as grouped flaccid vesicles that rupture easily, leaving behind crusted erosions and dry, scaly, eczematous patches.^17,18 Over time, velvety, fissured, and hypertrophic plaques develop. Up to 80% of patients experience secondary bacterial and fungal superinfections that may cause vegetative or malodorous plaques.⁹ Although HHD has no specific treatment, symptoms are managed with topical corticosteroids and antimicrobial agents. Patients should be advised to avoid irritants such as friction, sunlight, or sweat. For severe cases, botulinum toxin type A, laser therapy, dermabrasion, and surgery have been utilized with variable success.^19-22 The responsiveness of HHD to corticosteroids and antimicrobial agents facilitates misdiagnosis as intertrigo, erythrasma, or dermatophytosis.

Our patient presented with late-onset HHD (age, 50 years) compared to the typical age of onset in the third decade of life.⁸ Furthermore, her presentation was atypical for HHD, which characteristically affects intertriginous areas due to sweat, heat, friction, and microorganisms. Hailey-Hailey disease involving the abdominal skin is unusual, as it typically occurs in regions of friction such as the belt area.²³ Our patient lacked a history of friction or trauma at the site of the abdominal plaque. In addition, HHD involving the feet is exceedingly rare. It is plausible that friction and heat caused by footwear may have predisposed her to these skin changes.

Conclusion

This case highlights the difficulties of diagnosing HHD, especially if it appears in atypical locations.²⁴ Obtaining a thorough family history and detailed dermatologic examination as well as maintaining a high level of suspicion can assist in diagnosing this uncommon disorder.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Diffuse dermal angiomatosis (DDA) is a rare acquired, cutaneous, reactive, vascular disorder that was originally thought to be a variant of cutaneous reactive angiomatosis (CREA) but is now considered to be on the spectrum of CREA. This article will focus on DDA and review the literature of prior case reports with brief descriptions of the differential diagnosis.

Case Report

A 43-year-old Haitian man presented to the clinic with a lesion on the left buttock that had developed over the last 6 years. The patient stated the lesion had been enlarging over the last several months. Upon examination, there was a large (15-cm diameter), indurated, hyperpigmented plaque covering the left buttock (Figure 1). The patient reported no medical or contributory family history. Upon review of systems, he described a burning sensation sometimes in the area of the lesion that would develop randomly throughout the year.

Three biopsies were performed, which revealed a collection of slightly dilated blood vessels with normal-appearing endothelial cells occupying the mid dermis and deep dermis (Figure 2). Immunohistochemical stains with antibodies were directed against human herpesvirus 8 (HHV-8), CD31, CD34, the cell surface glycoprotein podoplanin, Ki-67, and smooth muscle actin antigens, with appropriate controls. The vessel walls were positive for CD31, CD34, and smooth muscle actin, and negative for HHV-8 and podoplanin; Ki-67 was not increased. These histologic findings were consistent with a diagnosis of DDA. A detailed history was taken. The cause of DDA in our patient was uncertain.

Comment

Classification and Epidemiology
Diffuse dermal angiomatosis is a rare acquired, cutaneous, reactive, vascular disorder first described by Krell et al¹ in 1994. Diffuse dermal angiomatosis is benign and is classified in the group of cutaneous reactive angiomatoses,² which are benign vascular disorders marked by intravascular and extravascular hyperplasia of endothelial cells that may or may not include pericytes.² Diffuse dermal angiomatosis was originally described as a variant of CREA, which is characterized by hyperplasia of endothelial dermal cells and intravascular proliferation.³ However, DDA has more recently been identified as a distinct disorder on the spectrum of CREA rather than as a variant of CREA.² Given the recent reclassification, not all physicians make this distinction. However, as more case reports of DDA are published, physicians continue to support this change.⁴ Nevertheless, DDA has been an established disorder since 1994.¹

Vascular proliferation in DDA is hypothesized to stem from ischemia or inflammation.⁵ Peripheral vascular atherosclerosis has been associated with DDA.⁶ The epidemiology of DDA is not well known because of the rarity of the disease. We performed a more specific review of the literature by limiting the PubMed search of articles indexed for MEDLINE to the term diffuse dermal angiomatosis rather than a broader search including all reactive angioendotheliomatoses. Only 31 case reports have been published^1,3-32; of them, only adults were affected. Most reported cases were in middle-aged females. A summary of the demographics of DDA is provided in the Table.^1,3-32

Etiology
Diffuse dermal angiomatosis is a rare complication of ischemia that may be secondary to atherosclerosis, arteriovenous fistula, or macromastia.^9-11 In DDA of the breasts, ulcerations of fatty tissue occur due to trauma in these patients who have large pendulous breasts, causing angiogenesis resembling DDA histologically.² One case of DDA was reported secondary to relative ischemia from cutis marmorata telangiectatica congenita,¹² whereas another case highlighted Wegener granulomatosis as the cause of ischemia.⁷ There also have been reported cases associated with calciphylaxis and anticardiolipin antibiodies.¹³ In general, any medical condition that can lead to ischemia can cause DDA. Comorbid conditions for DDA include cardiovascular disease, hypertension, diabetes mellitus, and most often severe peripheral vascular disease. Many patients also have a history of smoking.¹⁴ Diffuse dermal angiomatosis rarely presents without underlying comorbidity, with only 1 case report of unknown cause (Table).

Presentation, Histopathology, and Differential Diagnosis
Cutaneous reactive angiomatosis disorders present the same clinically, with multiple erythematous to violaceous purpuric patches and plaques that can progress to necrosis and ulceration. Lesions are widely distributed but are predisposed to the upper and lower extremities.² The differential diagnosis of DDA includes CREA, acroangiodermatitis (pseudo–Kaposi sarcoma), or vascular malignancies such as Kaposi sarcoma and low-grade angiosarcoma.⁷

In DDA, lesions may be painful and sometimes have a central ulceration.¹⁵ They often are associated with notable peripheral vascular atherosclerotic disease and are mainly found on the lower extremities.^12,16 Histologically, DDA presents as a diffuse proliferation of endothelial cells between collagen bundles. The endothelial cells are distributed throughout the papillary and reticular dermis and develop into vascular lumina.¹⁷ Furthermore, the proliferating endothelial cells are spindle shaped and contain vacuolated cytoplasm.¹⁴

Acroangiodermatitis, or pseudo–Kaposi sarcoma, presents as slow-growing, erythematous to violaceous, brown, or dusky macules, papules, or plaques of the legs.¹⁴ Histologically, acroangiodermatitis presents with relatively less proliferation of endothelial cells found intravascularly rather than extravascularly, as in DDA, forming new thick-walled vessels in a lobular pattern in the papillary dermis.¹⁴

Vascular malignancies, such as Kaposi sarcoma and angiosarcoma, may present similarly to DDA. Kaposi sarcoma, for example, presents as erythematous to violaceous patches, plaques, or nodules found mostly on the extremities.⁷ Histologically, spindle cells and vascular structures also are found but in a clefting pattern representative of Kaposi sarcoma (so-called vascular slits).⁷ Diffuse dermal angiomatosis and vascular malignancies can further be distinguished based on atypia of the proliferations and staining for HHV-8.^7,14 Lastly, DDA differs from vascular tumors in that vascular tumors are reactive to locations of occluded vessels, with vascular proliferation ceasing once the underlying cause of hypoxia is removed.²

Treatment
There is no standard treatment of DDA.⁷ Treatment of the underlying cause of ischemia is the primary goal, which will cause the DDA to resolve in most cases. Stenting, removal of an arteriovenous fistula, or other forms of revascularization may be warranted.^{1,5,6,10,17,29,30}

Reported medical therapies for DDA include systemic or topical corticosteroids used for their antiangiogenic properties with varying results.⁷ Isotretinoin also has been used, which has been found to be effective in several cases of DDA of the breast, though 1 study reported a subsequent elevated lipid profile, requiring a decrease in dosage.^14,15,27,31

Most interestingly, a study by Sanz-Motilva et al¹⁶ demonstrated that control of comorbidities, especially smoking cessation, led to improvement, which highlights the importance of incorporating nonpharmacotherapy rather than initiating treatment solely with medication. The Table summarizes treatments used and their efficacy.

Conclusion

Diffuse dermal angiomatosis is associated with medical conditions that predispose an individual to ischemia. Although rare, DDA can present as painful and visibly disturbing lesions that can affect the daily life of afflicted patients. By reporting the few cases that do arise and reviewing prior cases and their treatments, physicians can consider DDA within the differential diagnosis and identify which treatment is most efficient for a given patient. For all DDA patients, strict control of comorbidities, especially smoking cessation, should be incorporated into the treatment plan. When DDA affects the breasts, isotretinoin appears to provide the best relief. Otherwise, treatment of the underlying cause, revascularization, withdrawal of the offending agent, or steroids seem to be the best treatment options.

Case Presentation

An 80-year-old white male was evaluated in a primary care clinic following a recent hospitalization for a suicide attempt. His past medical history included type 2 diabetes mellitus, chronic atrial fibrillation, essential hypertension and hyperlipidemia, and no prior psychiatric illness. Six weeks after his wife died of cancer, the patient attempted suicide by slitting his wrists, which resulted in significant blood loss and tendon damage.

After medical stabilization he was treated at an inpatient psychiatric facility for 10 days. There was no evidence of impaired memory nor psychosis during his hospitalization. He was prescribed doxazosin 1 mg twice daily and finasteride 5 mg daily for obstructive urinary symptoms, along with escitalopram 5 mg daily for depression and continuation of prior medications, including glipizide 10 mg twice daily, simvastatin 20 mg daily, metformin 500 mg twice daily, and lisinopril 20 mg daily. The patient’s estimated glomerular filtration rate was 85 at the time of these events.

He was evaluated by the mental health staff at the time of his primary care outpatient visit and noted to have a Patient Health Questionnaire (PHQ-9) score of 5 (mild depression symptoms) and a Generalized Anxiety Disorder 7 Item Scale (GAD-7) score of 1 (minimum anxiety symptoms). Eleven days later during his counseling appointment, he mentioned to staff that he had experienced a painful erection the day before, which lasted 4 hours. The primary care pharmacist was consulted for review of potential medication triggers. It was noted that there was a low frequency of priapism with both doxazosin and escitalopram, a selective serotonin reuptake inhibitor (SSRI). The provider team felt that the α blocker (doxazosin) was more likely than was the SSRI to cause the reported priapism event. Doxazosin was discontinued, and escitalopram 5 mg daily was maintained. His mood remained stable with no further suicidal ideation.

Eighteen days after discontinuation of doxazosin, the patient experienced a second priapism episode. He reported 2 days later that he experienced a prolonged, painful erection that lasted 4 hours and resolved without intervention. The patient’s mood continued without further suicidal thoughts, his appetite was normal, he had good social support and played cards with friends regularly. At that time, the decision was made to discontinue the escitalopram. The SSRI was felt to be a possible cause of priapism due to the length of time off doxazosin in relation to the second event.

The patient continued to do well 15 months after discontinuation of these medications. Unfortunately, he did not seek medical care during either episode of priapism, but he was felt to be reliable in his report based on a normal mental status exam. He does not have any of the other known risk factors for priapism, suggesting a possible association with his α blocker and SSRI.

Discussion

Priapism is a prolonged, painful erection lasting more than 4 hours and is considered a urologic emergency. It is divided into ischemic and nonischemic types. Ischemic priapism occurs with blood dyscrasias, such as sickle cell disease, thalassemia, leukemia, neurologic conditions affecting the spinal cord, and malignancies of bladder/prostate. The lifetime probability of priapism in patients affected by sickle cell disease is estimated at 29% to 42%.¹ Medications associated with priapism include cocaine, ondansetron, antipsychotics, excessive use of erectile dysfunction drugs, and increasingly, antidepressants.^2-8

Nonischemic priapism is usually associated with pelvic trauma. Cavernous blood gas obtained at the time of the event can help distinguish between the 2 types. The color of the aspirated blood sample is black in patients with ischemic priapism. Corporal blood gas analysis shows hypoxemia and acidemia. The color of blood is red in patients with nonischemic priapism and shows normal oxygen and pH. Priapism is a urologic emergency requiring aspiration of blood from the cavernous sinus to prevent ischemic tissue damage. At times surgical decompression may be required if aspiration is not successful.

Adrenergic α-blocking agents were developed for treatment of hypertension. They have become popular for management of lower urinary tract symptoms (LUTS) secondary to prostate enlargement. Doxazosin, prazosin, and terazosin are nonuroselective and have a higher risk of cardiac adverse effects (AEs), including dizziness and orthostatic hypotension. Lexicomp lists < 1% incidence of priapism associated with doxazosin.⁹ The drug is metabolized by CYP3A4 with secondary pathways, including CYP2D6 and 2C9 with a drug half-life of 22 hours. Newer agents (eg, tamsulosin, alfuzosin) are considered more uroselective, targeting the α-1b receptors. The older agents have more effect on the α-1a receptors, which are also present at higher level in the cardiovascular system.¹⁰ By blocking sympathetic stimuli responsible for penile detumescence, the nonselective α blockers have a higher propensity to cause priapism. There seems to be a direct correlation between higher doses and increased risk of priapism.¹¹ Our patient was at a relatively low dose (1 mg twice daily) of the nonselective agent doxazosin for treatment of his LUTS.

Primary care providers and psychiatrists treating depression are familiar with common sexual AEs of the SSRI class of medications. Decreased sexual desire and delayed orgasm and ejaculation are all issues that lead patients to discontinue treatment. Although SSRIs are considered first-line treatment for depression, reports indicate that up to 60% of patients with prior normal sexual function started on paroxetine may experience sexual AEs.¹² The exact frequency is difficult to estimate due to underreporting of these issues by patients.

A review of the literature for cases of priapism associated with SSRIs shows that often there is more than 1 possible drug trigger, and medications used in combination may be a risk factor. It is hypothesized that SSRI action on 5-HT3 receptors may be responsible for priapism occurring in patients treated with SSRIs.¹³ One study cites a case of priapism in a veteran being treated with escitalopram, prazosin, and trazodone for posttraumatic stress disorder.¹⁴ Trazodone inhibits the neuronal uptake of serotonin and is used to treat depression in addition to off-label use in treatment of insomnia. Trazodone is implicated in cases of priapism via its α-blocking properties. In the aforementioned case, trazodone was initially thought to be the causative agent and was discontinued. The patient had recurrent symptoms at which time his prazosin was discontinued, and he had no further events.

Another case cites citalopram-induced priapism that occurred with an accidental overdose of citalopram 80 mg, when a patient confused his antidepressant with 81-mg aspirin tablets.¹⁵ He also had a prior history of priapism while taking trazodone. We found only 1 case listing escitalopram as the probable causative agent of priapism.¹⁶ Similar to our patient, that case had no risk factors prior to escitalopram administration. Lexicomp notes < 1% incidence of priapism reported in postmarketing studies.

Our patient had been off doxazosin for 18 days when his second event of priapism occurred. It is less likely given the half-life of doxazosin (t ½ = 22 hours) that the α blocker was the causative agent, though a combination of the 2 agents cannot be excluded as a significant factor. The Naranjo Score is an algorithm for determining the likelihood of whether an adverse drug reaction is due to the drug or other factors.¹⁷ Scoring ranks the event as probable, possible, or doubtful. This case scored +3 (+2 = appeared after suspected drug given, +1 = improved when drug discontinued), indicating possible association of escitalopram and priapism.

Conclusion

In view of the frequent use of SSRIs in treatment of depression, it may be prudent to advise patients of this uncommon but serious medication AE. Recent use of α blockers may be a risk factor in combination with SSRI therapy. Patients should be counseled to seek emergency care in the event of prolonged erection when discussing potential AEs of SSRI therapy.

Case Presentation

An 80-year-old white male was evaluated in a primary care clinic following a recent hospitalization for a suicide attempt. His past medical history included type 2 diabetes mellitus, chronic atrial fibrillation, essential hypertension and hyperlipidemia, and no prior psychiatric illness. Six weeks after his wife died of cancer, the patient attempted suicide by slitting his wrists, which resulted in significant blood loss and tendon damage.

After medical stabilization he was treated at an inpatient psychiatric facility for 10 days. There was no evidence of impaired memory nor psychosis during his hospitalization. He was prescribed doxazosin 1 mg twice daily and finasteride 5 mg daily for obstructive urinary symptoms, along with escitalopram 5 mg daily for depression and continuation of prior medications, including glipizide 10 mg twice daily, simvastatin 20 mg daily, metformin 500 mg twice daily, and lisinopril 20 mg daily. The patient’s estimated glomerular filtration rate was 85 at the time of these events.

He was evaluated by the mental health staff at the time of his primary care outpatient visit and noted to have a Patient Health Questionnaire (PHQ-9) score of 5 (mild depression symptoms) and a Generalized Anxiety Disorder 7 Item Scale (GAD-7) score of 1 (minimum anxiety symptoms). Eleven days later during his counseling appointment, he mentioned to staff that he had experienced a painful erection the day before, which lasted 4 hours. The primary care pharmacist was consulted for review of potential medication triggers. It was noted that there was a low frequency of priapism with both doxazosin and escitalopram, a selective serotonin reuptake inhibitor (SSRI). The provider team felt that the α blocker (doxazosin) was more likely than was the SSRI to cause the reported priapism event. Doxazosin was discontinued, and escitalopram 5 mg daily was maintained. His mood remained stable with no further suicidal ideation.

Eighteen days after discontinuation of doxazosin, the patient experienced a second priapism episode. He reported 2 days later that he experienced a prolonged, painful erection that lasted 4 hours and resolved without intervention. The patient’s mood continued without further suicidal thoughts, his appetite was normal, he had good social support and played cards with friends regularly. At that time, the decision was made to discontinue the escitalopram. The SSRI was felt to be a possible cause of priapism due to the length of time off doxazosin in relation to the second event.

The patient continued to do well 15 months after discontinuation of these medications. Unfortunately, he did not seek medical care during either episode of priapism, but he was felt to be reliable in his report based on a normal mental status exam. He does not have any of the other known risk factors for priapism, suggesting a possible association with his α blocker and SSRI.

Discussion

Priapism is a prolonged, painful erection lasting more than 4 hours and is considered a urologic emergency. It is divided into ischemic and nonischemic types. Ischemic priapism occurs with blood dyscrasias, such as sickle cell disease, thalassemia, leukemia, neurologic conditions affecting the spinal cord, and malignancies of bladder/prostate. The lifetime probability of priapism in patients affected by sickle cell disease is estimated at 29% to 42%.¹ Medications associated with priapism include cocaine, ondansetron, antipsychotics, excessive use of erectile dysfunction drugs, and increasingly, antidepressants.^2-8

Nonischemic priapism is usually associated with pelvic trauma. Cavernous blood gas obtained at the time of the event can help distinguish between the 2 types. The color of the aspirated blood sample is black in patients with ischemic priapism. Corporal blood gas analysis shows hypoxemia and acidemia. The color of blood is red in patients with nonischemic priapism and shows normal oxygen and pH. Priapism is a urologic emergency requiring aspiration of blood from the cavernous sinus to prevent ischemic tissue damage. At times surgical decompression may be required if aspiration is not successful.

Adrenergic α-blocking agents were developed for treatment of hypertension. They have become popular for management of lower urinary tract symptoms (LUTS) secondary to prostate enlargement. Doxazosin, prazosin, and terazosin are nonuroselective and have a higher risk of cardiac adverse effects (AEs), including dizziness and orthostatic hypotension. Lexicomp lists < 1% incidence of priapism associated with doxazosin.⁹ The drug is metabolized by CYP3A4 with secondary pathways, including CYP2D6 and 2C9 with a drug half-life of 22 hours. Newer agents (eg, tamsulosin, alfuzosin) are considered more uroselective, targeting the α-1b receptors. The older agents have more effect on the α-1a receptors, which are also present at higher level in the cardiovascular system.¹⁰ By blocking sympathetic stimuli responsible for penile detumescence, the nonselective α blockers have a higher propensity to cause priapism. There seems to be a direct correlation between higher doses and increased risk of priapism.¹¹ Our patient was at a relatively low dose (1 mg twice daily) of the nonselective agent doxazosin for treatment of his LUTS.

Primary care providers and psychiatrists treating depression are familiar with common sexual AEs of the SSRI class of medications. Decreased sexual desire and delayed orgasm and ejaculation are all issues that lead patients to discontinue treatment. Although SSRIs are considered first-line treatment for depression, reports indicate that up to 60% of patients with prior normal sexual function started on paroxetine may experience sexual AEs.¹² The exact frequency is difficult to estimate due to underreporting of these issues by patients.

A review of the literature for cases of priapism associated with SSRIs shows that often there is more than 1 possible drug trigger, and medications used in combination may be a risk factor. It is hypothesized that SSRI action on 5-HT3 receptors may be responsible for priapism occurring in patients treated with SSRIs.¹³ One study cites a case of priapism in a veteran being treated with escitalopram, prazosin, and trazodone for posttraumatic stress disorder.¹⁴ Trazodone inhibits the neuronal uptake of serotonin and is used to treat depression in addition to off-label use in treatment of insomnia. Trazodone is implicated in cases of priapism via its α-blocking properties. In the aforementioned case, trazodone was initially thought to be the causative agent and was discontinued. The patient had recurrent symptoms at which time his prazosin was discontinued, and he had no further events.

Another case cites citalopram-induced priapism that occurred with an accidental overdose of citalopram 80 mg, when a patient confused his antidepressant with 81-mg aspirin tablets.¹⁵ He also had a prior history of priapism while taking trazodone. We found only 1 case listing escitalopram as the probable causative agent of priapism.¹⁶ Similar to our patient, that case had no risk factors prior to escitalopram administration. Lexicomp notes < 1% incidence of priapism reported in postmarketing studies.

Our patient had been off doxazosin for 18 days when his second event of priapism occurred. It is less likely given the half-life of doxazosin (t ½ = 22 hours) that the α blocker was the causative agent, though a combination of the 2 agents cannot be excluded as a significant factor. The Naranjo Score is an algorithm for determining the likelihood of whether an adverse drug reaction is due to the drug or other factors.¹⁷ Scoring ranks the event as probable, possible, or doubtful. This case scored +3 (+2 = appeared after suspected drug given, +1 = improved when drug discontinued), indicating possible association of escitalopram and priapism.

Conclusion

In view of the frequent use of SSRIs in treatment of depression, it may be prudent to advise patients of this uncommon but serious medication AE. Recent use of α blockers may be a risk factor in combination with SSRI therapy. Patients should be counseled to seek emergency care in the event of prolonged erection when discussing potential AEs of SSRI therapy.

Case Presentation

An 80-year-old white male was evaluated in a primary care clinic following a recent hospitalization for a suicide attempt. His past medical history included type 2 diabetes mellitus, chronic atrial fibrillation, essential hypertension and hyperlipidemia, and no prior psychiatric illness. Six weeks after his wife died of cancer, the patient attempted suicide by slitting his wrists, which resulted in significant blood loss and tendon damage.

After medical stabilization he was treated at an inpatient psychiatric facility for 10 days. There was no evidence of impaired memory nor psychosis during his hospitalization. He was prescribed doxazosin 1 mg twice daily and finasteride 5 mg daily for obstructive urinary symptoms, along with escitalopram 5 mg daily for depression and continuation of prior medications, including glipizide 10 mg twice daily, simvastatin 20 mg daily, metformin 500 mg twice daily, and lisinopril 20 mg daily. The patient’s estimated glomerular filtration rate was 85 at the time of these events.

He was evaluated by the mental health staff at the time of his primary care outpatient visit and noted to have a Patient Health Questionnaire (PHQ-9) score of 5 (mild depression symptoms) and a Generalized Anxiety Disorder 7 Item Scale (GAD-7) score of 1 (minimum anxiety symptoms). Eleven days later during his counseling appointment, he mentioned to staff that he had experienced a painful erection the day before, which lasted 4 hours. The primary care pharmacist was consulted for review of potential medication triggers. It was noted that there was a low frequency of priapism with both doxazosin and escitalopram, a selective serotonin reuptake inhibitor (SSRI). The provider team felt that the α blocker (doxazosin) was more likely than was the SSRI to cause the reported priapism event. Doxazosin was discontinued, and escitalopram 5 mg daily was maintained. His mood remained stable with no further suicidal ideation.

Eighteen days after discontinuation of doxazosin, the patient experienced a second priapism episode. He reported 2 days later that he experienced a prolonged, painful erection that lasted 4 hours and resolved without intervention. The patient’s mood continued without further suicidal thoughts, his appetite was normal, he had good social support and played cards with friends regularly. At that time, the decision was made to discontinue the escitalopram. The SSRI was felt to be a possible cause of priapism due to the length of time off doxazosin in relation to the second event.

The patient continued to do well 15 months after discontinuation of these medications. Unfortunately, he did not seek medical care during either episode of priapism, but he was felt to be reliable in his report based on a normal mental status exam. He does not have any of the other known risk factors for priapism, suggesting a possible association with his α blocker and SSRI.

Discussion

Priapism is a prolonged, painful erection lasting more than 4 hours and is considered a urologic emergency. It is divided into ischemic and nonischemic types. Ischemic priapism occurs with blood dyscrasias, such as sickle cell disease, thalassemia, leukemia, neurologic conditions affecting the spinal cord, and malignancies of bladder/prostate. The lifetime probability of priapism in patients affected by sickle cell disease is estimated at 29% to 42%.¹ Medications associated with priapism include cocaine, ondansetron, antipsychotics, excessive use of erectile dysfunction drugs, and increasingly, antidepressants.^2-8

Nonischemic priapism is usually associated with pelvic trauma. Cavernous blood gas obtained at the time of the event can help distinguish between the 2 types. The color of the aspirated blood sample is black in patients with ischemic priapism. Corporal blood gas analysis shows hypoxemia and acidemia. The color of blood is red in patients with nonischemic priapism and shows normal oxygen and pH. Priapism is a urologic emergency requiring aspiration of blood from the cavernous sinus to prevent ischemic tissue damage. At times surgical decompression may be required if aspiration is not successful.

Adrenergic α-blocking agents were developed for treatment of hypertension. They have become popular for management of lower urinary tract symptoms (LUTS) secondary to prostate enlargement. Doxazosin, prazosin, and terazosin are nonuroselective and have a higher risk of cardiac adverse effects (AEs), including dizziness and orthostatic hypotension. Lexicomp lists < 1% incidence of priapism associated with doxazosin.⁹ The drug is metabolized by CYP3A4 with secondary pathways, including CYP2D6 and 2C9 with a drug half-life of 22 hours. Newer agents (eg, tamsulosin, alfuzosin) are considered more uroselective, targeting the α-1b receptors. The older agents have more effect on the α-1a receptors, which are also present at higher level in the cardiovascular system.¹⁰ By blocking sympathetic stimuli responsible for penile detumescence, the nonselective α blockers have a higher propensity to cause priapism. There seems to be a direct correlation between higher doses and increased risk of priapism.¹¹ Our patient was at a relatively low dose (1 mg twice daily) of the nonselective agent doxazosin for treatment of his LUTS.

Primary care providers and psychiatrists treating depression are familiar with common sexual AEs of the SSRI class of medications. Decreased sexual desire and delayed orgasm and ejaculation are all issues that lead patients to discontinue treatment. Although SSRIs are considered first-line treatment for depression, reports indicate that up to 60% of patients with prior normal sexual function started on paroxetine may experience sexual AEs.¹² The exact frequency is difficult to estimate due to underreporting of these issues by patients.

A review of the literature for cases of priapism associated with SSRIs shows that often there is more than 1 possible drug trigger, and medications used in combination may be a risk factor. It is hypothesized that SSRI action on 5-HT3 receptors may be responsible for priapism occurring in patients treated with SSRIs.¹³ One study cites a case of priapism in a veteran being treated with escitalopram, prazosin, and trazodone for posttraumatic stress disorder.¹⁴ Trazodone inhibits the neuronal uptake of serotonin and is used to treat depression in addition to off-label use in treatment of insomnia. Trazodone is implicated in cases of priapism via its α-blocking properties. In the aforementioned case, trazodone was initially thought to be the causative agent and was discontinued. The patient had recurrent symptoms at which time his prazosin was discontinued, and he had no further events.

Another case cites citalopram-induced priapism that occurred with an accidental overdose of citalopram 80 mg, when a patient confused his antidepressant with 81-mg aspirin tablets.¹⁵ He also had a prior history of priapism while taking trazodone. We found only 1 case listing escitalopram as the probable causative agent of priapism.¹⁶ Similar to our patient, that case had no risk factors prior to escitalopram administration. Lexicomp notes < 1% incidence of priapism reported in postmarketing studies.

Our patient had been off doxazosin for 18 days when his second event of priapism occurred. It is less likely given the half-life of doxazosin (t ½ = 22 hours) that the α blocker was the causative agent, though a combination of the 2 agents cannot be excluded as a significant factor. The Naranjo Score is an algorithm for determining the likelihood of whether an adverse drug reaction is due to the drug or other factors.¹⁷ Scoring ranks the event as probable, possible, or doubtful. This case scored +3 (+2 = appeared after suspected drug given, +1 = improved when drug discontinued), indicating possible association of escitalopram and priapism.

Conclusion

In view of the frequent use of SSRIs in treatment of depression, it may be prudent to advise patients of this uncommon but serious medication AE. Recent use of α blockers may be a risk factor in combination with SSRI therapy. Patients should be counseled to seek emergency care in the event of prolonged erection when discussing potential AEs of SSRI therapy.

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.